Project Summary/Abstract: Spinal cord injury (SCI) is a major health care issue in our Veteran population. While rehabilitation medicine provides for some therapeutic improvement for SCI there are no medical interventions that lead to protection of neural tissue or induce regenerative responses. However, a number of cell therapy and small molecule approaches to both protect and promote regeneration have been successful in pre-clinical studies using animal models. Intravenous infusions of bone marrow-derived mesenchymal/stromal stem cells (MSCs) have been demonstrated to produce beneficial effects in repairing tissue damage. Intravenous infusion of MSCs also has beneficial effects in a number of experimental neurological disorders including stroke and spinal cord injury. In some injury or disease models the therapeutic effects of MSC transplantation have been replicated by transplantation of exosomes produced by these MSCs. Exosomes are nanosphere membrane bound particles containing proteins and mRNAs/miRNAs which are highly stable and are capable of being taken up by other cells and altering their function. These recently characterized secreted cellular nanospheres are believed to play an important role in cell-cell communication in both health and disease. Preliminary studies in our lab have found that intravenous infusion of exosomes produced by cultured MSCs can replicate therapeutic effects of MSC infusion in spinal cord injured rats including improved locomotor function and decreased vascular leakage in the spinal cord within one week after intravenous infusion. We propose to determine if these beneficial effects observed early in SCI are sustained and how they compare to MSC infusion. The overall objective of this project is to evaluate the therapeutic potential of intravenously delivered MSC-derived exosomes for spinal cord injury (SCI). Exosomes are more stable and storable than cells and pose no risk of aneuploidy and have a lower possibility of immune rejection. The preclinical work we propose here is directed to provide basic information on safety and the potential therapeutic effects of intravenously delivered MSC- derived exosomes in the context of potential future clinical studies in SCI patients. We currently have ongoing clinical trials in both SCI and stroke using autologous MSCs, and success with the proposed studies could facilitate the development of a clinical study using MSC-derived exosomes for SCI.